Sympazan

Dosing Information

A daily dose of SYMPAZAN®  greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability. Each dose in Table 1 (e.g., 5 to 20 mg in 30 kg or less weight group) has been shown to be effective, although effectiveness increases with increasing dose [see Clinical Studies (14)]. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state.

Discontinuation or Dosage Reduction of SYMPAZAN

To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue SYMPAZAN or reduce the dosage. Taper by decreasing the total daily dosage by 5-10 mg/day on a weekly basis until discontinued. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

Important Administration Instructions

Instruct patients and/or caregivers to read the “Instructions for Use” carefully for complete directions on how to properly dose and administer SYMPAZAN® oral films.

Apply SYMPAZAN®  on top of the tongue where it adheres and dissolves.

SYMPAZAN® oral film can be taken with or without food [see Clinical Pharmacology (12.3)]. Do not administer with liquids. As the film dissolves, saliva should be swallowed in a normal manner, but the patient should refrain from chewing, spitting or talking.

Only one oral film should be taken at a time; if a second film is needed to complete the dosage, it should not be taken until the first film has completely dissolved.

Dosage Adjustments in Geriatric Patients

Plasma concentrations at any given dose are generally higher in geriatric patients [see Clinical Pharmacology (12.3)]. Therefore, the starting dosage should generally be 5 mg/day for all geriatric patients. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.5)].

Dosage Adjustments in CYP2C19 Poor Metabolizers

In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased [see Clinical Pharmacology (12.5)]. Therefore, the starting dosage should be 5 mg/day in patients known to be CYP2C19 poor metabolizers. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.6)].

Dosage Adjustments in Patients with Hepatic Impairment

SYMPAZAN®  is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of SYMPAZAN®. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dosage should be 5 mg/day (regardless of weight). Then proceed slowly with dosing escalations; titrate patients according to weight, but to half the dosage presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21. There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment. Therefore, no dosing recommendation can be given for those patients [see Use in Specific Populations (8.8), Clinical Pharmacology (12 .3)].

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN®, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN® enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at http://www.aedpregnancyregistry.org/

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.9) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data). Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [see Animal Data].

Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15% -20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses. The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day.

Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.

Oral administration of clobazam (0, 50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryofetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behavior (locomotor activity) at all doses. The low-effect dose for adverse effects on preand postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam lower than those in humans at the MRHD.

Lactation

Risk Summary

SYMPAZAN® is excreted in human milk (see Data). There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of clobazam on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYMPAZAN® and any potential adverse effects on the breastfed infant from SYMPAZAN® or from the underlying maternal condition.

Clinical Considerations

Adverse reactions such as somnolence and difficulty feeding have been reported in infants during breastfeeding in postmarketing experience with clobazam. Infants exposed to SYMPAZAN through breast milk should be monitored for sedation, poor feeding and poor weight gain.

Data

Scientific literature on clobazam use during lactation is limited. After short-term administration, clobazam and N-desmethylclobazam are transferred into breast milk.

Females and Males of Reproductive Potential

Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)].

Pediatric Use

Safety and effectiveness for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in pediatric patients 2 years of age and older have been established in two adequate and well-controlled studies [see Clinical Studies (14)].

Safety and effectiveness in patients less than 2 years of age have not been established.

Juvenile Animal Data

In a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.

Geriatric Use

Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, dosage modification is recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

CYP2C19 Poor Metabolizers

Concentrations of clobazam's active metabolite, N-desmethylclobazam, are higher in CYP2C19 poor metabolizers than in extensive metabolizers. For this reason, dosage modification is recommended [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Renal Impairment

The pharmacokinetics of clobazam were evaluated in patients with mild and moderate renal impairment. There were no significant differences in systemic exposure (AUC and Cmax) between patients with mild or moderate renal impairment and healthy subjects. No dose adjustment is required for patients with mild and moderate renal impairment. There is essentially no experience with SYMPAZAN® in patients with severe renal impairment or ESRD. It is not known if clobazam or its active metabolite, N-desmethyl-clobazam, is dialyzable [see Clinical Pharmacology (12.3)].

Hepatic Impairment

SYMPAZAN® is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of clobazam. For this reason, dosage adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9) [see Dosage and Administration (2.6)]. There is inadequate information about metabolism of SYMPAZAN® in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].